Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient

ABSTRACT

The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)and also the preparation and use of the crystalline polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I).

The present invention relates to a novel and improved process forpreparing(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (I)

and also the preparation and use of the crystalline polymorph I of(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (I).

The compound of the formula (I) acts as a non-steriodal antagonist ofthe mineralocorticoid receptor and may be used as an agent forprophylaxis and/or treatment of cardiovascular and renal disorders suchas heart failure and diabetic nephropathy, for example.

The compound of the formula (I) and the preparation process thereof aredescribed in WO 2008/104306 and ChemMedChem 2012, 7, 1385, in which adetailed discussion of the synthetic research is disclosed in bothpublications. A disadvantage of the synthesis described therein is thefact that this synthesis is unsuitable for a further large-scaleprocess, since many steps proceed at very high dilution, with very highexcesses of reagents and therefore afford a relatively low overallyield. Furthermore, many intermediate chromatographic purifications arenecessary, which are technically generally very laborious and entail ahigh consumption of solvents, which are costly and are therefore to beavoided if possible. Some stages are not achievable due to safety andprocess technology difficulties.

There existed a need, therefore, for an industrially practicablesynthesis, which affords the compound of the formula (I) in areproducible manner in high overall yield, low production costs and highpurity and meets all regulatory requirements, in order to provideclinical trials with active ingredient and to be used for laterregulatory submission.

In terms of the present invention, a very efficient synthesis has beenfound which allows the requirements mentioned above to be met.

In the publication ChemMedChem 2012, 7, 1385, which discloses theresearch scale synthesis of the compound of the formula (I), thecompound of the formula (I) is prepared in 10 stages starting fromvanillin with an overall yield of 3.76% of theory. The compound of theformula (I) was obtained by evaporation of chromatographic fractions asan amorphous solid; a defined crystallisation process for the finalstage for polymorphic adjustment has not been described to date.

The following scheme 1 shows the known process for preparing thecompound of the formula (I).

Three chromatographic purifications are utilised and also a chiralchromatography stage for separating the enantiomers of the racemate ofthe formula (XIII). Some of the stages proceed at very high dilution andusing very large amounts of reagent.

For instance, the sequence of the preparation of the nitrile-aldehydeintermediate (VI) in particular, which takes on a central role in thissynthesis, is unacceptable in terms of atom economy.

Furthermore, this process cannot be transferred to an industrial scalesince first of all very expensive reagents are used, such astrifluoromethanesulphonic anhydride [(III)=>(IV)] and excesses oftert-butyl acrylate. On scaling up the Heck reaction (IV)=>(V), aresidue similar to plastic forms in the tank, which originates from thepolymerisation of the tert-butyl acrylate used in excess. This isunacceptable in an industrial procedure, since the danger exists that itcan cause a fracture of the stirrer and would lead to residues in thestirrer mechanism that are too hard to remove.

The subsequent cleavage of the double bond with sodium periodate and thehighly toxic osmium tetroxide should also be avoided since, under theexperimental conditions described, a delay of the reaction occurs andresults in a strong exothermicity and therefore links to a runawayreaction.

Scheme 2 illustrates the novel process according to the invention, whichaffords the compound of the formula (I) in 9 stages in an overall yieldof 27.7% of theory without chromatographic purification ofintermediates.

The methyl ester (XV) and the aldehyde (XVI) are not isolated but arefurther reacted directly in solution, which results in only 7 stages tobe isolated. A preparative chiral HPLC method (e.g. SMB Technology,Varicol) is used for the enantiomer separation.

The aldehyde (VI) is known from the literature (J. Med. Chem. 2007, 50,2468-2485) and is an important intermediate in this synthesis.Meanwhile, there is also the possibility to purchase the compoundcommercially.

Starting from 4-cyano-2-methoxytoluene (VIa), a dibromide (VIb) isprepared with NBS, which is reacted in ethanol with 2.46 eq. of silvernitrate (in water) to the target aldehyde (VI). This synthesis describedin the literature and the process described in the research scalesynthesis are completely unsuitable for scaling up to the multi-tonnescale such that a great need existed for a novel, more efficient andeconomically more viable synthesis.

The halobenzoic acids (XIV) and (XIVa)

are commercially available in relatively large amounts. A very efficientand cheaper process has been developed in which the intermediates (XV)and (XVI)

are not isolated but are further reacted dissolved in solution. This isonly possible because the yield and purity of each reaction is very high(>95% of theory). The methyl ether ester (XV) is known from theliterature (Journal of Medicinal Chemistry, 1992, vol. 35, p. 734-740)and is prepared by reaction with the highly volatile, harmful to healthand expensive methyl iodide.

With the new process according to the invention it was possible to showthat the non-volatile, less expensive dimethyl sulphate can be usedanalogously. Starting from the acid (XIV), said acid is reacted in asolvent such as acetone, 2-butanone, THF, 2-methyl-THF, DMF, DMA or NMPwith dimethyl sulphate with the aid of an auxiliary base such aspotassium carbonate, sodium carbonate, calcium carbonate, lithiumcarbonate, N-methylimidazole, triethylamine, pyridine or 2,6-lutidine attemperatures of 50-100° C. to give the methyl ether ester (XV). Methodsknown to those skilled in the art here are esterification of acids andetherification of phenols (Tetrahedron, 2013, vol. 69, p. 2807-2815,Journal of the American Chemical Society, 2013, vol. 135, p. 5656-5668).The reaction in acetone under reflux (56° C.) using dimethyl sulphateand potassium carbonate has been found to be particularly preferred. Inthis case, dimethyl sulphate is added to the boiling reaction mixtureover 4 hours. The acetone is distilled off and replaced by toluene(redistillation). For the work-up, water is added (decomposing theexcess dimethyl sulphate), the toluene phase is separated and washedwith water and saturated sodium chloride solution and the toluenesolution subsequently distilled off to a certain volume (serves asazeotropic drying, i.e. removal of water for the subsequent stage).Determination of the solution content shows virtually completeconversion (>96% of theory). Instead of the bromine compound, thechlorine compound may be used analogously for which the achievedconversions are identical to the bromine compound.

The preparation of the aldehyde (XVI) is described in the literature,examples of which include: Glaxo Group Limited US2008/312209 A1, 2008,European Journal of Medicinal Chemistry, 1986, vol. 21, p. 397-402,Journal of Medicinal Chemistry, 1992, vol. 35, p. 734-740, Journal ofMaterials Chemistry, 2011, vol. 21, p. 9523-9531. However, the startingmaterials used in the reactions are very expensive and not obtainable inlarge amounts, therefore a new method starting from the methyl etherester (XV) was developed. The conversion of (XV) to the aldehyde (XVI)is possible using REDAL (sodium bis(2-methoxyethoxy)aluminium dihydride)in toluene by addition of N-methylpiperazine. This method is describedin the literature (Synthesis 2003, No. 6, 823-828 and Tetrahedron 57(2001) 2701-2710). If the reaction is carried out analogously to thestoichiometry stated in the literature, a further compound is found inthe mixture in addition to the aldehyde. It was shown that this is thecorresponding benzyl alcohol which is formed by overreduction of up to10%. It was shown that it is important to adjust the stoichiometry ofthe REDAL and N-methylpiperazine to exactly 1.21 eq. of REDAL+1.28 eq.of N-methylpiperazine, making it possible to reduce this by-product,which disrupts the crystallization in the subsequent stage, to <1%. Forthis purpose, a 65% REDAL solution in toluene at 0-5° C. is charged(preferably 1.21 eq.) and 1.28 eq. of N-methylpiperazine is added. Thesolution of REDAL with N-methylpiperazine thus obtained is added overca. 30 minutes to the bromo methyl ester solution (XIV) charged intoluene and the mixture is subsequently stirred for one hour at 0° C.The reaction solution is quenched in water/acid, preferably aqueoussulphuric acid and the toluene phase is separated and washed with waterand saturated sodium chloride solution. The toluene is distilled off andredistilled in DMF (solvent for the subsequent stage). The reactionyield is generally >94% of theory. The corresponding reaction with thechloro compound proceeds analogously and the yields are equivalent. TheDMF solution is used directly in the subsequent reaction.

In the further course of the synthesis, the bromoaldehyde (XVI) isconverted to the nitrile in a manner known per se by methods familiar tothose skilled in the art (Synth. Commun. 1994, 887-890, Angew. Chemie2003, 1700-1703, Tetrahedron Lett. 2007, 2555-2557, Tetrahedron Lett.2004, 1441-1444, JACS 2003, 125, 2890-2891, Journal of OrganometallicChemistry 689 (2004), 4576-4583), where in this case the nitrilealdehyde (VI) is obtained. It has proven particularly advantageous inthe case of the bromo compound to carry out a palladium-catalysedreaction with potassium hexacyanoferrate*3 H₂O as the cyanide source(Tetrahedron Lett. 48 (2007), 1087-1090). For this purpose, thebromoaldehyde (XVI) is charged in DMF (8-10 fold), 0.22 eq. of potassiumhexacyanoferrate*3 H₂O and 1 eq. of sodium carbonate is charged and then0.005 eq. of palladium acetate is added. The mixture is heated to 120°C. for 3 hours. The solution is cooled to 20° C., then water and ethylacetate is added. The ethyl acetate phase is separated off, the waterphase washed again with ethyl acetate and the combined ethyl acetatephases then redistilled in isopropanol. The product precipitates bywater precipitation at the boiling temperature. After isolation, theproduct is dried under vacuum. In some cases, the product wasprecipitated directly by addition of water to the DMF and used directlyin the subsequent stage after isolation and drying. The reaction yieldsare generally >85% of theory. Palladium acetate is not adequate for theconversion of the chloro compound and it has proven advantageous in thiscase to use the palladium catalysts familiar to those skilled in theart, such as is described in Tetrahedron Lett. 48 (2007), 1087-1090,where the yields are somewhat lower than with the bromo compound,generally 80-85% of theory.

The cinnamic ester (VIII a,b) is obtained as an E/Z mixture startingfrom the aldehyde of the formula (VI) by a Knoevenagel reaction with thecyanoester (VIII):

In the research directive, 16.6 fold dichloromethane and 0.2 eq. ofpiperidine/0.2 eq. of glacial acetic acid were heated for 20 hours on awater separator. After aqueous work-up, the product is crystallized frommethanol after evaporation of the solvent, the target compound beingobtained at 52% of theory.

The reaction proceeds preferably in boiling dichloromethane (10-fold) byaddition of 5-20 mol % of piperidine, preferably 10 mol % and 5-20 mol %of glacial acetic acid, preferably 5-10 mol %, on a water separator. Thereaction time is 4-12 h, but preferably 5-6 h, particularly preferably 6h. 1.0-1.5 eq, preferably however 1.1 to 1.35 eq. or 1.25 eq to 1.35 eqof the cyanoester (VII) is added. With particular preference 1.1 eq. isadded. The preparation of the cyanoester (VII) is described inPharmazie, 2000, vol. 55, p. 747-750 and Bioorg. Med. Chem. Lett. 16,798-802 (2006). After completion, the reaction is cooled to 20° C. andthe organic phase is washed twice with water. The organic wash isredistilled in 2-butanol and the E/Z cinnamic ester mixture (VIII a+b)is used directly without intermediate isolation in the subsequentreaction with the heterocycle (IX) to give the dihydropyridine (X):

For the further reaction in the research scale synthesis, the mixturewas heated under reflux with the heterocycle (IX) in isopropanol for 40hours.

It has been found that the reaction may be carried out, preferably in asecondary alcohol such as isopropanol, isobutanol, 2-amyl alcohol orcyclohexanol at temperatures of 80-160° C., at atmospheric pressure andalso in autoclaves (2-10 bar), with reaction times of 8-40 h, butpreferably for 20-25 h in boiling 2-butanol at atmospheric pressure orelse in isopropanol in an autoclave (100° C., 2-10 bar, preferably 3-5bar, 8-24 h). For work-up, the mixture is cooled to 0° C. to 20° C., thecrystals filtered off and washed with isopropanol and then dried (invacuum, 60° C.).

If the use of dichloromethane should be omitted for environmentallyeconomic reasons, it has proven to be advantageous to prepare thecinammic ester (VIII a,b) in isopropanol, in which case the aldehyde(VI) is charged in isopropanol (3-9 fold, preferably 5-7 fold) and 5-20mol % of piperidine, preferably 5-10 mol %, 10 mol % and 5-20 mol % ofglacial acetic acid, preferably 5-10 mol % or 10 mol % is added. At 30°C., 1.0-1.5 eq, preferably 1.1-1.35 eq. or 1.35 eq., particularlypreferably 1.1 eq. of cyanoester (VII) is added over 3 hours, optionallydissolved in a little isopropanol, and the mixture is stirred at 30° C.for 1 hour. The cinammic ester (VIIIa,b) crystallizes out during thereaction. The product is subsequently filtered off, optionally aftercooling, preferably at 0° C., washed with a little isopropanol (cooledto 0° C.) and used moist in the subsequent reaction as described above.The yield is >96% of theory. The subsequent reaction is preferablyperformed in 10-15 fold (with respect to aldehyde (VI)), preferably11-12 fold isopropanol for 20-24 hours at 100° C. under pressure. Aftertermination of the reaction and cooling, the product is isolated byfiltration or centrifugation. The product is subsequently dried at40-90° C. under vacuum. Since the conversion to the cinammic esterproceeds virtually quantitatively, the process for the subsequent stagecan be readily standardised without having to adjust the amount ofheterocyle (IX) in each case, as the product can be used moist withisopropanol. The yields are >87% of theory. The heterocycle (IX) can beprepared by known literature methods such as is described, for example,in Synthesis 1984, 765-766.

Starting from the dihydropyridine (X), the ethyl ether (XI) is obtainedby reaction under acidic catalysis with an orthoester, where R is —H or-methyl:

In the research scale synthesis, the reaction was carried out in 25 foldDMF with 20.2 eq. of triethyl orthoformate and catalytic amounts ofconc. sulphuric acid at 135° C. The mixture was concentrated to drynessand the residue was purified by chromatography with a yield of 86% oftheory. This method is unsuitable as a technical procedure due to thehigh dilution and the use of triethyl orthoformate, highly flammable atlow temperature, which is used in very large excess, and the subsequentchromatography.

It has been found, surprisingly, that the reaction can be carried outhighly concentrated (up to 1.5 g of solvent per 1 g of reactant) insolvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF(dimethylformamide) by addition of 4-10% by weight, preferably 6-8% byweight, of conc. sulphuric acid. The reaction proceeds, surprisingly,even with 2.5-5 eq. or 5 eq. of orthoester. It has been found that it ismuch more convenient to use the corresponding triethyl orthoacetate inthe reaction, since it reacts much more cleanly on the one hand and ismuch less inflammable, making it particularly appropriate for thetechnical procedure. The reaction is preferably carried out in DMA(dimethylacetamide) and/or NMP (1-methyl-2-pyrrolidone), at temperaturesof 100-120° C., preferably 115° C. Before starting the actual reaction,it has proven advantageous to distill off some of the solvent (DMAand/or NMP) at elevated temperature (100-120° C. under vacuum) in orderto remove any residues of isopropanol present from the precursor, asotherwise undesirable by-products occur. Reaction: Stir for 1.5-3 hours,preferably 2 hours. For the work-up, water is added directly to themixture, wherein the product crystallizes out. In order to have aparticularly stable and reproducible process, a portion of the water(e.g. ⅓) is first added, then it is seeded, and the remaining amount ofthe water is added. This procedure guarantees that the same crystalpolymorph is always obtained, which shows the optimum isolationcharacteristics. The product is washed with water and dried. The yieldsare >92% of theory.

Starting from the ethyl ether (XI), the acid (XII) is obtained byalkaline saponification and subsequent acidic work-up.

In the research scale synthesis, the saponification was carried out athigh dilution (33.9 fold) in a mixture of DME/water 3:1. Here, it wasessential primarily to increase throughput and to replace the DME(dimethoxyethane) used, which has a very low flash point and istherefore considered to be particularly critical for large-scale use. Ithas been found, surprisingly, that the reaction can also be conductedvery readily highly concentrated in mixtures of THF/water. For thispurpose, the reaction is preferably performed in a mixture of THF/water2:1 (9-fold), the aqueous sodium hydroxide solution is added at 0-5° C.,then the mixture is stirred at 0-5° C. for 1-2 hours. Aqueous potassiumhydroxide can also be used but NaOH is preferably used. For the work-up,the mixture is extracted with MTBE (methyl tert-butyl ether) and ethylacetate and for the isolation the pH is adjusted with a mineral acidsuch as hydrochloric acid, sulphuric acid or phosphoric acid, butpreferably hydrochloric acid, to pH 6.5-7.0 or pH 7. The mixture is thenmixed with saturated ammonium salt solution of the corresponding acid,but preferably ammonium chloride solution, wherein the productquantitatively crystallizes out. After isolation, the product is washedwith water and with ethyl acetate or acetonitrile or acetone, butpreferably acetonitrile, and dried under vacuum at 40-50° C. The yieldis virtually quantitative (99%). Alternative preferred work-up: As analternative work-up, toluene is added to the mixture, sodium acetate isadded and the mixture is stirred at 20° C., the phases are thenseparated and the aqueous phase is adjusted at 0° C. with 10% aqueoushydrochloric acid to pH 6.5-7.0 (may optionally be seeded at pH 9.5-10).The mixture is briefly stirred and the product filtered off, washed witha little water and toluene and dried at 40-50° C. under vacuum. Theyields achieved are also quantitative in this case.

The subsequent conversion of the acid to the amide (XIII) was carriedout in the research stage as follows: The acid (XII) was dissolved inca. 10-fold DMF, 1.25 eq. of 1,1′-carbodiimidazole and 0.1 eq. of DMAP(4-(dimethylamino)pyridine) were added and the mixture was stirred atroom temperature for 4 hours. Subsequently, 20 eq. of ammonia in theform of an aqueous 25% solution were added and this mixture transferredto an oilbath pre-heated to 110° C. In this procedure, relatively largeamounts of ammonia gas form instantaneously, which escape the system andin addition ensure a sharp increase in pressure. This mixture was addedto ca. 90-fold water and adjusted to pH 7 by addition of sodium acetate.The precipitated product was filtered off and dried (yield: 59% oftheory). A further portion was isolated from the mother liquor byexhaustive extraction (ca. 100 fold ethyl acetate), which was stirredwith highly flammable diethyl ether and comprised ca. 14% DMF. It isclear that such a method cannot be achieved in such a manner in anoperational framework and therefore there is a high demand for analternative procedure. The effort required for the isolation of thisportion is disproportionate to the amount isolated in this case.

It has been found, surprisingly, that in the reaction of the acid (XII)in THF, the amide (XIII) crystallises out directly from the solution andcan be obtained in high yield and purity. For this purpose, thecarboxylic acid (XII) in THF is reacted with 1.1 to 1.6 eq., preferably1.3-1.4 eq. of 1,1′-carbodiimidazole under DMAP catalysis (5-15 mol %,preferably 10 mol %) to give the imidazolide, which takes place attemperatures between 20-50° C., the preferred approach having proven tobe initially starting at 20° C., then stirring 1 to 2 hours at thistemperature and then further stirring at 50° C. for 2 to 3 hours. Aftercompletion of the activation, 3-8 eq, preferably 4.5 eq. ofhexamethyldisilazane is added and the mixture is boiled under reflux for16-24 hours, but preferably 16 hours. The resulting disilylamidecompound here can optionally be isolated but it has been proven to beadvantageous to continue in a one-pot reaction. Therefore, on completionof the reaction, the mixture is cooled to 0-3° C. and a mixture ofwater/or in a mixture with THF is added, it having proven to beadvantageous to use an amount of water of 0.5 to 0.7 fold (with respectto reactant), particularly advantageous being an amount of water of 0.52fold. The water can be added directly or as a mixture with approximatelyan equivalent up to double the amount of THF by volume. After quenchingis complete, the mixture is heated under reflux for 1-3 hours in total,preferably 1 hour. The mixture is cooled to 0° C. and stirred for 1-5hours, preferably 3 hours, at this temperature, then the product isisolated by filtration or centrifugation. The product is washed with THFand water and dried under vacuum at elevated temperature (30 to 100° C.,preferably at 60° C. to 90° C. or at 40° C. to 70° C.). The yields arevery high and are generally >93% of theory. The purity is generally >99%(HPLC, 100% method). The compound (XIII) may also be obtained directlyby reacting with ammonia gas in the autoclave (ca. 25 to 30 bar). Forthis purpose, the preactivation described above is carried out and thereaction mixture is heated under pressure under gaseous ammonia. Oncompletion of the reaction, it is cooled and the product filtered off.The yields and purities thus achieved are comparable.

To obtain the compound of the formula (I), the racemic mixture of amides(XIII) must be separated into the antipodes. In the published researchscale synthesis, a specifically synthesized chiral phase was used forthis purpose (prepared in-house), which comprisedN-(dicyclopropylmethyl)-N²-methacryloyl-D-leucinamide as chiralselector. This selector was prepared in a multi-stage process and thenpolymerized on special silica gel. Methanol/ethyl acetate served aseluent. A major disadvantage of this method was the very low loading, 30mg per separation on a 500*63 mm chromatography column, such that therewas a high need to find as effective a separation method as possiblewhich allows separation of antipodes to be performed in the multi-tonnerange. It has been found, surprisingly, that the separation can beperformed on a readily commercially available phase. This takes the formof the phase Chiralpak AS-V, 20 μm. The eluent used was a mixture ofmethanol/acetonitrile 60:40. This mixture has the major advantage thatit can be recovered as eluent after distillative work-up having theidentical composition (60:40 corresponds to the azeotrope. A veryefficient process is achieved in this way in which the yield of theseparation is >47% of theory (50% is theoretically possible). Theoptical purity here is >93% e.e. but preferably >98.5% e.e. In thiscase, the chromatography may be carried out on a conventionalchromatography column, but preferably the techniques known to thoseskilled in the art such as SMB or Varicol (Computers and ChemicalEngineering 27 (2003) 1883-1901) are used. For instance, ca. 500 kg ofthe racemic amide (XIII) was separated using an SMB system, in which ayield of 48% was achieved. The product is obtained as a 3-8%, preferably5-7% solution in a mixture of methanol/acetonitrile 60:40 and can beused directly in “final processing”. Other solvent mixture ratios ofacetonitrile to methanol are also conceivable (90:10 to 10:90).Alternatively, other solvent mixtures can also be used, however, for theSMB separation, such as acetonitrile/ethanol in mixture ratios of 10:90to 90:10. The particular solvent ratio depends partly on the technicalproperties of the SMB system and must be adjusted, if appropriate (e.g.varying flow rate, recycling of the solvent on a thin film evaporator).

Since the compound of the formula (I) has been developed in the form ofa tablet, there exists a high demand that the isolated compound of theformula (I) is isolated in a defined crystalline form in a reproduciblemanner such that a reproducible bioavailability can be ensured. It hasbeen found, surprisingly, that the compound of the formula (I) can becrystallized from methanol, ethanol, THF, acetonitrile, and alsomixtures thereof with water, wherein only one polymorph I isreproducibly formed, which has a defined melting point of 252° C. By wayof advantage, ethanol or denatured ethanol is used.

Final crystallization process: For this purpose, the ca. 5-7% productsolution in methanol/acetonitrile 60:40 (or, if ethanol/acetonitrile wasemployed, a ca. 3-4% solution of ethanol/acetonitrile 50:50) originatingfrom the chromatography is firstly subjected to a particle filtrationfor GMP technical reasons and subsequently a solvent exchange withethanol is performed, preferably using ethanol denatured with toluene.For this purpose, the solution is repeatedly redistilled, concentratedand fresh ethanol added each time. After exchange, as much ethanol isadded until a solution phase is passed through at the boiling point andthen it is concentrated under atmospheric pressure or under slightlyreduced pressure to ca. 3 to 4 fold by volume, whereupon the productcrystallizes out. This is cooled to 0° C. and the crystals then isolatedand dried at 40-50° C. under vacuum. The yields are generally >90% oftheory. The chemical purity achieved is >99.8% and the content ˜100%correspond to the criteria for commercial products according to ICHguidelines. Residual solvent, in the case of ethanol, is <0.02%. Theoptical purity is >>99% e.e.

The present invention provides the compound of the formula (I) incrystalline form of polymorph I

characterized in that the x-ray diffractogram of the compound exhibitspeak maxima of the 2 theta angle at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6,26.5.

The present invention further provides the compound of the formula (I)in crystalline form of polymorph I

characterized in that the IR spectrum (IR-ATR) of the compound exhibitsband maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and1031 cm⁻¹.

The present invention further provides the compound of the formula (I)in crystalline form of polymorph I

characterized in that the Raman spectrum of the compound exhibits bandmaxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155cm⁻¹.

The present invention further provides a process for preparing thecompound of the formula (I) in crystalline form of polymorph I,characterized in that the compound of the formula (I), present in one ormore polymorphs or as a solvate in an inert solvent, is stirred at atemperature of 20° C.-120° C. and the compound of the formula (I) isisolated in crystalline polymorph I.

Preferred solvents for the process for preparing the compound of theformula (I) in crystalline form of polymorph I are methanol, ethanol,THF, acetonitrile, and also mixtures thereof. Particular preference isgiven to ethanol or denatured ethanol.

A preferred temperature range for the process for preparing the compoundof the formula (I) in crystalline form of polymorph I is from 20° C. to90° C.

The present invention further provides a compound of the formula (I) incrystalline form of polymorph (I) as described above for treatment ofdisorders.

The present invention further provides a medicament comprising acompound of the formula (I) in crystalline form of polymorph (I) asdescribed above and no greater proportions of any other form of thecompound of the formula (I) in crystalline form of polymorph (I) asdescribed above. The present invention further provides a medicamentcomprising a compound of the formula (I) in crystalline form ofpolymorph (I) as described above in more than 90 percent by weight basedon the total amount of the compound of the formula (I) present incrystalline form of polymorph (I) as described above.

The present invention further provides for the use of the compound ofthe formula (I) in crystalline form of polymorph I as described above.To prepare a medicament for the treatment of cardiovascular disorders.

The present invention further provides the method for treatment ofcardiovascular disorders by administering an effective amount of acompound of the formula (I) in crystalline form of polymorph (I) asdescribed above.

The present invention further provides a process for preparing compound(I), characterized in that the compound of the formula (XIV) or theformula (XIVa)

are reacted by addition of dimethyl sulphate to give the compound of theformula (XV) or (XVa)

and the non-isolated methyl esters of the formula (XV) or (XVa) arereduced with 1.21 eq of REDAL (solution bis(2-methoxyethoxy)aluminiumdihydride and 1.28 eq of N-methylpiperazine to give the aldehyde of theformula (XVI) or (XVIa)

and the aldehyde (XVI) or (XVIa) is reacted further without isolation togive the nitrile of the formula (VI)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b).

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XII)

is reacted in a one-pot reaction in THF firstly with carbodiimidazoleand catalytic amounts of 4-(dimethylamino)pyridine, in a second step isheated under reflux together with hexamethyldisilazane for 16 to 24hours and in a third step is hydrolysed in water with THF or water togive the compound of the formula (XIII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XIV) or the formula (XIVa)

are reacted by addition of dimethyl sulphate to give the compound of theformula (XV) or (XVa)

and the non-isolated methyl esters of the formula (XV) or (XVa) arereduced with 1.21 eq of REDAL (sodium bis(2-methoxyethoxy)aluminiumdihydride and 1.28 eq of N-methylpiperazine to give the aldehyde of theformula (XVI) or (XVIa)

and the aldehyde (XVI) or (XVIa) is reacted further without isolation togive the nitrile of the formula (VI)

and the compound of the formula (VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperdine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b).

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

and that the compound of the formula (XII)

is reacted in a one-pot reaction in THF firstly with carbodiimidazoleand catalytic amounts of 4-(dimethylamino)pyridine, in a second step isheated under reflux together with hexamethyldisilazane for 16 to 24hours and in a third step is hydrolysed in water with THF or water togive the compound of the formula (XIII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XIV) or the formula (XIVa)

are reacted by addition of dimethyl sulphate to give the compound of theformula (XV) or (XVa)

and the non-isolated methyl esters of the formula (XV) or (XVa) arereduced with 1.21 eq of REDAL (sodium bis(2-methoxyethoxy)aluminiumdihydride and 1.28 eq of N-methylpiperazine to give the aldehyde of theformula (XVI) or (XVIa)

and the aldehyde (XVI) or (XVIa) is reacted further without isolation togive the nitrile of the formula (VI)

and the compound of the formula (VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

and that the compound of the formula (XII)

is reacted in a one-pot reaction in THF firstly with carbodiimidazoleand catalytic amounts of 4-(dimethylamino)pyridine, in a second step isheated under reflux together with hexamethyldisilazane for 16 to 24hours and in a third step is hydrolysed in water with THF or water togive the compound of the formula (XIII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XIV) or the formula (XIVa)

are reacted by addition of dimethyl sulphate to give the compound of theformula (XV) or (XVa)

and the non-isolated methyl esters of the formula (XV) or (XVa) arereduced with 1.21 eq of REDAL (sodium bis(2-methoxyethoxy)aluminiumdihydride and 1.28 eq of N-methylpiperazine to give the aldehyde of theformula (XVI) or (XVIa)

and the aldehyde (XVI) or (XVIa) is reacted further without isolation togive the nitrile of the formula (VI)

and the compound of the formula (VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

and that the compound of the formula (XII)

is reacted in a one-pot reaction in THF firstly with carbodiimidazoleand catalytic amounts of 4-(dimethylamino)pyridine, in a second step isheated under reflux together with hexamethyldisilazane for 16 to 24hours and in a third step is hydrolysed in water with THF or water togive the compound of the formula (XIII)

The present invention further provides a process for preparing compoundof the formula (I), characterized in that the compound of the formula(XIV) or the formula (XIVa)

are reacted by addition of dimethyl sulphate to give the compound of theformula (XV) or (XVa)

and the non-isolated methyl esters of the formula (XV) or (XVa) arereduced with 1.21 eq of REDAL (sodium bis(2-methoxyethoxy)aluminiumdihydride and 1.28 eq of N-methylpiperazine to give the aldehyde of theformula (XVI) or (XVIa)

and the aldehyde (XVI) or (XVIa) is reacted further without isolation togive the nitrile of the formula (VI)

and the compound of the formula (VI)

dissolved in isopropanol (3-7 fold), 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. is reacted with the compound ofthe formula (VII)

to give the compounds (VIIIa+b)

and that the compound of the formula (X)

is reacted while stirring with 2.5-5 eq of triethyl orthoacetate indimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give thecompound of the formula (XI)

and that the compound of the formula (XI)

is saponified in a THF/water mixture (2:1, 9-fold) with aqueous sodiumhydroxide solution to give the compound of the formula (XII)

and that the compound of the formula (XII)

is reacted in a one-pot reaction in THF firstly with carbodiimidazoleand catalytic amounts of 4-(dimethylamino)pyridine, in a second step isheated under reflux together with hexamethyldisilazane for 16 to 24hours and in a third step is hydrolysed in water with THF or water togive the compound of the formula (XIII)

The crystallization process is very robust and affords the compound ofthe formula I in crystalline form of polymorph I in a reproduciblemanner (m.p. 252° C.). Surprisingly, it is also possible to use materialwith lower optical purities in the crystallization process and it wasshown that even a material of 93% e.e. still gives rise aftercrystallization to >99% e.e.

The compound of the formula (I) is generally micronized and to beformulated into the pharmaceutical. It is found that the compound of theformula (I) in crystalline form of polymorph I has very good stabilityproperties (even at high atmospheric humidity) and can be stored withoutany problem for >2 years.

With the novel synthesis according to the invention, it is possible toprepare the compound of the formula (I) in a very efficient manner. Theprocess offers considerable advantages compared to the prior artrelating to scalability and technical performance. The overall yield issignificantly higher compared to published data and excellent puritiesof the active ingredient are also achieved. The novel process enablesthe reproducible, economic preparation of the defined compound of theformula (I) in crystalline form of polymorph I, of which the existencein the prior art has nowhere been described.

Using the process according to the invention presented here, 200 kg ofmaterial has already been successfully prepared for clinical trials.

The compounds according to the invention, the compound of the formula(I) and of which the compound of the formula (I) in crystalline form ofpolymorph I act as antagonists of the mineralocorticoid receptor andexhibit an unforeseeable, useful spectrum of pharmacological activity.They are therefore suitable for use as medicaments for treatment and/orprophylaxis of disorders in humans and animals.

The inventive compounds are suitable for the prophylaxis and/ortreatment of various disorders and disease-related conditions,especially of disorders characterized either by an increase in thealdosterone concentration in the plasma or by a change in thealdosterone plasma concentration relative to the renin plasmaconcentration, or associated with these changes. Examples include:idiopathic primary hyperaldosteronism, hyperaldosteronism associatedwith adrenal hyperplasia, adrenal adenomas and/or adrenal carcinomas,hyperaldosteronism associated with cirrhosis of the liver,hyperaldosteronism associated with heart failure, and (relative)hyperaldosteronism associated with essential hypertension.

The inventive compounds are also suitable, because of their mechanism ofaction, for the prophylaxis of sudden cardiac death in patients atincreased risk of dying of sudden cardiac death. In particular, theseare patients who suffer, for example, from any of the folllowingdisorders: primary and secondary hypertension, hypertensive heartdisease with or without congestive heart failure, treatment-resistanthypertension, acute and chronic heart failure, coronary heart disease,stable and unstable angina pectoris, myocardial ischaemia, myocardialinfarction, dilative cardiomyopathies, inherited primarycardiomyopathies, for example Brugada syndrome, cardiomyopathies causedby Chagas disease, shock, arteriosclerosis, atrial and ventriculararrhythmia, transient and ischaemic attacks, stroke, inflammatorycardiovascular disorders, peripheral and cardiac vascular disorders,peripheral blood flow disturbances, arterial occlusive disorders such asintermittent claudication, asymptomatic left-ventricular dysfunction,myocarditis, hypertrophic changes to the heart, pulmonary hypertension,spasms of the coronary arteries and peripheral arteries, thromboses,thromboembolic disorders, and vasculitis.

The inventive compounds can also be used for the prophylaxis and/ortreatment of edema formation, for example pulmonary oedema, renal oedemaor heart failure-related oedema, and of restenoses such as followingthrombolysis therapies, percutaneous transluminal angioplasties (PTA)and percutaneous transluminal coronary angioplasties (PTCA), hearttransplants and bypass operations.

The inventive compounds are further suitable for use as apotassium-saving diuretic and for electrolyte disturbances, for examplehypercalcaemia, hypernatraemia or hypokalaemia.

The inventive compounds are equally suitable for treatment of renaldisorders, such as acute and chronic renal failure, hypertensive renaldisease, arteriosclerotic nephritis (chronic and interstitial),nephrosclerosis, chronic renal insufficiency and cystic renal disorders,for prevention of renal damage which can be caused, for example, byimmunosuppressives such as cyclosporin A in the case of organtransplants, and for renal cancer.

The inventive compounds can additionally be used for the prophylaxisand/or treatment of diabetes mellitus and diabetic sequelae, for exampleneuropathy and nephropathy.

The inventive compounds can also be used for the prophylaxis and/ortreatment of microalbuminuria, for example caused by diabetes mellitusor high blood pressure, and of proteinuria.

The inventive compounds are also suitable for the prophylaxis and/ortreatment of disorders associated either with an increase in the plasmaglucocorticoid concentration or with a local increase in theconcentration of glucocorticoids in tissue (e.g. of the heart). Examplesinclude: adrenal dysfunctions leading to overproduction ofglucocorticoids (Cushing's syndrome), adrenocortical tumours withresulting overproduction of glucocorticoids, and pituitary tumours whichautonomously produce ACTH (adrenocorticotropic hormone) and thus lead toadrenal hyperplasias with resulting Cushing's disease.

The inventive compounds can additionally be used for the prophylaxisand/or treatment of obesity, of metabolic syndrome and of obstructivesleep apnoea.

The inventive compounds can also be used for the prophylaxis and/ortreatment of inflammatory disorders caused for example by viruses,spirochetes, fungi, bacteria or mycobacteria, and of inflammatorydisorders of unknown etiology, such as polyarthritis, lupuserythematosus, peri- or polyarteritis, dermatomyositis, scleroderma andsarcoidosis.

The inventive compounds can further be employed for the treatment ofcentral nervous disorders such as depression, states of anxiety andchronic pain, especially migraine, and for neurodegenerative disorderssuch as Alzheimer's disease and Parkinson's syndrome.

The inventive compounds are also suitable for the prophylaxis and/ortreatment of vascular damage, for example following procedures such aspercutaneous transluminal coronary angioplasty (PTCA), implantation ofstents, coronary angioscopy, reocclusion or restenosis following bypassoperations, and for endothelial dysfunction, for Raynaud's disease, forthromboangiitis obliterans (Buerger' s syndrome) and for tinnitussyndrome.

The present invention further provides for the use of the compoundsaccording to the invention for treatment and/or prevention of disorders,especially the aforementioned disorders.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prevention of disorders, in particular the disorders mentionedabove.

The present invention further provides a process for treatment and/orprevention of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The compounds according to the invention can be used alone or, ifrequired, in combination with other active compounds. The presentinvention furthermore provides medicaments containing at least one ofthe compounds according to the invention and one or more further activecompounds, in particular for treatment and/or prevention of theabovementioned disorders. Preferred examples of active compoundssuitable for combinations include:

-   -   active compounds which lower blood pressure, for example and        with preference from the group of calcium antagonists,        angiotensin AII antagonists, ACE inhibitors, endothelin        antagonists, renin inhibitors, alpha-receptor blockers,        beta-receptor blockers and Rho kinase inhibitors;    -   diuretics, especially loop diuretics, and thiazides and        thiazide-like diuretics;    -   antithrombotic agents, by way of example and with preference        from the group of the platelet aggregation inhibitors, the        anticoagulants or the profibrinolytic substances;    -   active compounds altering lipid metabolism, for example and with        preference from the group of the thyroid receptor agonists,        cholesterol synthesis inhibitors such as, by way of example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, the ACAT inhibitors, CETP inhibitors, MTP        inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists,        cholesterol absorption inhibitors, lipase inhibitors, polymeric        bile acid adsorbents, bile acid reabsorption inhibitors and        lipoprotein(a) antagonists;    -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-I, and inhaled NO;    -   compounds having a positive inotropic effect, for example        cardiac glycosides (digoxin), beta-adrenergic and dopaminergic        agonists such as isoproterenol, adrenaline, noradrenaline,        dopamine and dobutamine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2,        3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil,        vardenafil and tadalafil, and PDE 3 inhibitors such as amrinone        and milrinone;    -   natriuretic peptides, for example “atrial natriuretic peptide”        (ANP, anaritide), “B-type natriuretic peptide” or “brain        natriuretic peptide” (BNP, nesiritide), “C-type natriuretic        peptide” (CNP) and urodilatin;    -   calcium sensitizers, a preferred example being levosimendan;    -   NO-independent but haem-dependent stimulators of guanylate        cyclase, such as especially the compounds described in WO        00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;    -   NO- and haem-independent activators of guanylate cyclase, such        as especially the compounds described in WO 01/19355, WO        01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO        02/070510;    -   inhibitors of human neutrophil elastase (HNE), for example        sivelestat or DX-890 (Reltran);    -   compounds which inhibit the signal transduction cascade, for        example tyrosine kinase inhibitors, especially sorafenib,        imatinib, gefitinib and erlotinib; and/or    -   compounds which influence the energy metabolism of the heart,        preferred examples being etomoxir, dichloroacetate, ranolazine        or trimetazidine.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, by way ofexample and with preference furosemide, bumetanide, torsemide,bendroflumethiazide, chlorthiazide, hydrochlorthiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide,chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamterene.

Agents which lower blood pressure are preferably understood to meancompounds from the group of calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, endothelin antagonists, renin inhibitors,alpha-receptor blockers, beta-receptor blockers, Rho kinase inhibitors,and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,by way of example and with preference nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an angiotensin AII antagonist,preferred examples being losartan, candesartan, valsartan, telmisartanor embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, byway of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, by way of example and with preference bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a renin inhibitor, preferred examplesbeing aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker, by way of example and with preference propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a rho kinaseinhibitor, by way of example and with preference fasudil, Y-27632,SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Antithrombotic agents (antithrombotics) are preferably understood tomean compounds from the group of platelet aggregation inhibitors, ofanticoagulants or of profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, by way of example and with preference aspirin,clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,by way of example and with preference ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, by way of example and with preference tirofiban orabciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, by way of example and with preference rivaroxaban (BAY59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban,fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982,MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, by way of example and with preference coumarin.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbents, bile acidreabsorption inhibitors, lipase inhibitors and the lipoprotein(a)antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor, byway of example and with preference torcetrapib (CP-529 414), JJT-705,BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, by way of example and with preference D-thyroxin,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins, by way of example and withpreference lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, by way of example and with preference BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor, byway of example and with preference avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a PPAR-delta agonist, preferredexamples being GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, by way of example and with preference ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,by way of example and with preference orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent, by way of example and with preference cholestyramine,colestipol, colesolvam, CholestaGel or colestimide. In a preferredembodiment of the invention, the compounds according to the inventionare administered in combination with a bile acid reabsorption inhibitor,by way of example and with preference ASBT (=IBAT) inhibitors, forexample AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, by way of example and with preference gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, non-toxic, pharmaceutically suitable excipients, andthe use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

The compounds according to the invention can be administered in suitableadministration forms for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art and release the compounds according tothe invention rapidly and/or in a modified manner and which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, for example tablets (uncoated or coated tablets,for example with gastric juice-resistant or retarded-dissolution orinsoluble coatings which control the release of the compound accordingto the invention), tablets or films/oblates which disintegrate rapidlyin the oral cavity, films/lyophilizates, capsules (for example hard orsoft gelatin capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished with avoidance of aresorption step (for example by an intravenous, intraarterial,intracardiac, intraspinal or intralumbar route) or with inclusion of aresorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Administrationforms suitable for parenteral administration include preparations forinjection and infusion in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/oblates or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Oral and parenteral administration are preferred, especially oral andintravenous administration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be accomplished in a mannerknown per se by mixing with inert, non-toxic, pharmaceutically suitableexcipients. These excipients include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), colorants (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of from about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and veryparticularly preferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, specifically as a function of body weight, route ofadministration, individual response to the active compound, nature ofthe preparation and time or interval over which administration takesplace. Thus, in some cases less than the abovementioned minimum amountmay be sufficient, while in other cases the upper limit mentioned mustbe exceeded. In the case of administration of greater amounts, it may beadvisable to divide them into several individual doses over the day.

The working examples which follow illustrate the invention. Theinvention is not restricted to the examples.

Unless stated otherwise, the percentages in the tests and examples whichfollow are percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentration data for the liquid/liquidsolutions are in each case based on volume.

EXPERIMENTAL PART

Abbreviations and Acronyms

-   MS: mass from mass spectrometry-   HPLC: high-performance liquid chromatography-   DMF: dimethylformamide-   Red-A1 solution in toluene: sodium bis(2-methoxyethoxy) aluminium    dihydride in toluene-   THF: tetrahydrofuran-   Aqu. HCl: aqueous hydrochloric acid-   DMAP: 4-(dimethylamino)pyridine

EXAMPLES Example 1 Methyl 4-bromo-2-methoxybenzoate (XV)

3.06 kg (22.12 mol) of potassium carbonate are initially charged in 3.6l of acetone and heated to reflux. To this suspension are added 1.2 kgof 4-bromo-2-hydroxybenzoic acid (5.53 mol), suspended in 7.8 l ofacetone and is further rinsed with 0.6 l of acetone. The suspension isheated under reflux for 1 hour (vigorous evolution of gas!). 2.65 kg(21.01 mol) of dimethyl sulphate are then added over 4 hours whileboiling. The mixture is subsequently stirred under reflux for 2.5 hours.The solvent is largely distilled off (to the point of stirrability) and12 l of toluene are added and the residual acetone is then distilled offat 110° C. About 3 l of distillate are distilled off, this beingsupplemented by addition of a further 3 l of toluene to the mixture. Themixture is allowed to cool to 20° C. and 10.8 l of water are added andvigorously stirred in. The organic phase is separated off and theaqueous phase is extracted once more with 6.1 l of toluene. The combinedorganic phases are washed with 3 l of saturated sodium chloride solutionand the toluene phase is concentrated to ca. 4 l. Determination of thecontent by evaporation of a portion results in a converted yield of1.306 kg (96.4% of theory). The solution is used directly in thesubsequent stage.

HPLC method A: RT ca. 11.9 min.

MS (EIpos): m/z=245 [M+H]⁺

¹H NMR (400 MHz, CD₂Cl₂): δ=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m,2H), 7.62 (d, 1H).

Example 2 4-Bromo-2-methoxybenzaldehyde (XVI)

1.936 kg (6.22 mol) of a 65% Red-A1 solution in toluene is charged with1.25 l of toluene at −5° C. To this solution is added 0.66 kg (6.59 mol)of 1-methylpiperazine, which is rinsed with 150 ml of toluene, keepingthe temperature between −7 and −5° C. The mixture is then allowed tostir at 0° C. for 30 minutes. This solution is then added to a solutionof 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV),dissolved in 4 l of toluene, keeping the temperature at −8 to 0° C.After further rinsing twice with 0.7 l of toluene, the mixture is thenstirred at 0° C. for 1.5 hours. For the work-up, the solution is addedto cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc.sulphuric acid). The temperature should increase at maximum to 10° C.(slow addition). The pH is adjusted to pH 1, if necessary, by additionof further sulphuric acid. The organic phase is separated off and theaqueous phase is extracted with 7.61 of toluene. The combined organicphases are washed with 5.1 l of water and then substantiallyconcentrated and the residue taken up in 10 l of DMF. The solution isagain concentrated to a volume of ca. 5 l. Determination of the contentby evaporation of a portion results in a converted yield of 1.041 kg(94.1% of theory). The solution is used directly in the subsequentstage.

HPLC method A: RT ca. 12.1 min.

MS (EIpos): m/z=162 [M+H]⁺

¹H-NMR (CDC₃, 400 MHz): δ=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d),10.40 (1H, s)

Example 3 4-Formyl-3-methoxybenzonitrile (VI)

719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in4.5 l of DMF are charged with 313 g (0.74 mol) of potassiumhexacyanoferrate (K₄[Fe(CN)₆]) and 354 g (3.34 mol) of sodium carbonateand a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetateare added. The mixture is stirred at 120° C. for 3 hours. The mixture isallowed to cool to 20° C. and 5.7 l of water is added to the mixture.The mixture is extracted with 17 l of ethyl acetate and the aqueousphase washed once more with 17 l of ethyl acetate. The organic phasesare combined and substantially concentrated, taken up in 5 l ofisopropanol and concentrated to ca. 2 l. The mixture is heated toboiling and 2 l of water added dropwise. The mixture is allowed to coolto 50° C. and 2 l of water added anew. The mixture is cooled to 3° C.and stirred at this temperature for one hour. The product is filteredoff and washed with water (2 times 1.2 l). The product is dried at 40°C. under vacuum.

Yield: 469 g (87% of theory) of a beige solid.

HPLC method A: RT ca. 8.3 min.

MS (EIpos): m/z=162 [M+H]+

1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H),7.81 (d, 1H), 10.37 (s, 1H).

Example 4 2-Cyanoethyl4-(4-cyano-2-methoxyphenol)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-3-carboxylate(X)

Variant A

1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg(8.028 mol) of 2-cyanoethyl 3-oxobutanoate, 54.6 g (0.642 mol) ofpiperidine and 38.5 g (0.642 mol) of glacial acetic acid are heatedunder reflux in 10 l of dichloromethane for 6.5 hours on a waterseparator. The mixture is allowed to cool to room temperature and theorganic phase is washed twice with 5 l of water each time. Thedichloromethane phase is then concentrated at atmospheric pressure andthe still stirrable residue is taken up in 15.47 kg of 2-butanol and0.717 kg (5.78 mol) of 4-amino-5-methylpyridone is added. The residualdichloromethane is distilled off until an internal temperature of 98° C.is reached. The mixture is subsequently heated under reflux for 20hours. The mixture is cooled to 0° C., allowed to stir at thistemperature for 4 hours and the product is filtered off. The product isdried at 40° C. under vacuum under entraining gas.

Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridone,since this component is used substoichiometrically) of a pale yellowsolid.

HPLC method A: RT ca. 9.7 min.

MS (EIpos): m/z=405 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H),3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H),7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

Variant B

1.344 kg (8.34 mol) of 4-formyl-3-methoxybenzonitrile (VI), 71 g (0.834mol) of piperidine and 50.1 g (0.834 mol) of glacial acetic acid arecharged in 6 l of isopropanol and at 30° C. a solution of 1.747 kg(11.26 mol) of 2-cyanoethyl 3-oxobutanoate in 670 ml of isopropanol isadded over 3 hours. The mixture is then stirred at 30° C. for one hour.The mixture is cooled to 0-3° C. and stirred for 0.5 hours. The productis filtered off and washed twice with 450 ml of cold isopropanol eachtime. To determine the yield, the product is dried at 50° C. undervacuum (2.413 kg, 97% of theory); however, due to the high yield, theisopropanol-moist product is generally further processed directly. Forthis purpose, the product is taken up in 29 l of isopropanol and 1.277kg (7.92 mol) of 4-amino-5-methylpyridone are added and then the mixtureis heated to an internal temperature of 100° C. under a positivepressure of ca. 1.4 bar for 24 h in a closed vessel. The mixture is thencooled to 0° C. by means of a gradient over a period of 5 h and thenstirred at 0° C. for 3 hours. The product is then filtered off andwashed with 2.1 l of cold isopropanol. The product is dried at 60° C.under vacuum.

Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridone, sincethis component is used substoichiometrically) of a pale yellow solid.

HPLC method A: RT ca. 9.7 min.

MS (EIpos): m/z=405 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H),3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H),7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

Example 5 2-Cyanoethyl4-(4-cyano-2-methoxyphenol)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate(XI)

2.142 kg (5.3 mol) of 2-cyanoethyl4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate(X) and 4.70 kg (29 mol) of triethyl orthoacetate are dissolved in 12.15l of dimethylacetamide and 157.5 g of concentrated sulphuric acid areadded. The mixture is heated at 115° C. for 1.5 hours and then cooled to50° C. At 50° C., 12.15 l of water are added dropwise over 30 minutes.After completion of the addition, the mixture is seeded with 10 g of thetitle compound (XI) and a further 12.15 l of water are added dropwiseover 30 minutes at 50° C. The mixture is cooled to 0° C. (gradient, 2hours) and stirred at 0° C. for two hours. The product is filtered off,washed twice with 7.7 l each time of water and dried at 50° C. undervacuum.

Yield: 2114.2 g (92.2% of theory) of a pale yellow solid.

HPLC method B: RT ca. 10.2 min.

MS (EIpos): m/z=433 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H),2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d,1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

Alternatively, the reaction may be carried out in NMP(1-methyl-2-pyrrolidone)

2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate(XI)

2.142 kg (5.3 mol) of 2-cyanoethyl4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate(X) and 2.35 kg (14.5 mol) of triethyl orthoacetate are dissolved in3.21 kg of NMP (1-methyl-2-pyrrolidone) and 157.5 g of concentratedsulphuric acid are added. The mixture is heated at 115° C. for 1.5 hoursand then cooled to 50° C. At 50° C., 2.2 l of water are added dropwiseover 30 minutes. After completion of the addition, the mixture is seededwith 10 g of the title compound (XI) and a further 4.4 l of water areadded dropwise over 30 minutes at 50° C. The mixture is cooled to 0° C.(gradient, 2 hours) and then stirred at 0° C. for two hours. The productis filtered off, washed twice with 4 l each time of water and dried at50° C. under vacuum.

Yield: 2180.7 g (95.1% of theory) of a pale yellow solid.

HPLC method B: RT ca. 10.2 min.

Example 64-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid (XII)

2.00 kg (4.624 mol) of 2-cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate(XI) are dissolved in a mixture of 12 l of THF and 6 l of water andcooled to 0° C. To this solution at 0° C. is added dropwise over 15minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is thenstirred at 0° C. for 1.5 hours. The mixture is extracted twice with 4.8l of methyl tert-butyl ether each time and once with 4.8 l of ethylacetate. The aqueous solution at 0° C. is adjusted to pH 7 with dilutehydrochloric acid (prepared from 0.371 kg of 37% HCl and 1.51 l ofwater). The solution is allowed to warm to 20° C. and an aqueoussolution of 2.05 kg of ammonium chloride in 5.54 l of water is added.The solution is stirred at 20° C. for 1 hour, the product filtered andwashed twice with 1.5 l of water each time and once with 4 l ofacetonitrile. The product is dried at 40° C. under entraining gas.

Yield: 1736.9 g (99% of theory) of an almost colourless powder (verylight yellow tint).

HPLC method C: RT: ca. 6.8 min.

MS (EIpos): m/z=380 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H),3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H),7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

Alternative work-up using toluene for the extraction:

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid (XII)

2.00 kg (4.624 mol) of 2-cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate(XI) are dissolved in a mixture of 12 l of THF and 6 l of water andcooled to 0° C. To this solution at 0° C. is added dropwise over 15minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is thenstirred at 0° C. for 1.5 hours. 5 L of toluene and 381.3 g of sodiumacetate are added and stirred in vigorously. The phases are allowed tosettle and the organic phase is separated. The aqueous phase is adjustedto pH 6.9 with 10% hydrochloric acid (at ca. pH 9.5 the solution isseeded with 10 g of the title compound). After precipitation of theproduct is complete, the mixture is stirred at 0° C. for one hour and isthen filtered and washed twice with 4 l of water each time and twicewith 153 ml of toluene each time. The product is dried at 40° C. undervacuum under entraining gas (nitrogen, 200 mbar. Yield: 1719.5 g (98% oftheory) of an almost colourless powder (very slight yellow tint).

HPLC method C: RT: ca. 6.8 min.)

Example 74-(4-Cyano-2-methoxyphenol)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(XIII)

1.60 kg (4.22 mol) of4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid (XII) and 958 g (5.91 mol) of 1,1-carbodiimidazole are charged in 8l of THF and 51 g (0.417 mol) of DMAP is added at 20° C. The mixture isstirred at 20° C. (evolution of gas!) for one hour and then heated to50° C. for 2.5 hours. 2.973 kg (18.42 mol) of hexamethyldisilazane isadded to this solution and is boiled under reflux for 22 hours. Afurther 1.8 l of THF is added and the mixture cooled to 5° C. A mixtureof 1.17 l of THF and 835 g of water is added over 3 hours such that thetemperature remains between 5 and 20° C. The mixture is subsequentlyboiled under relux for one hour, then cooled via a gradient (3 hours) to0° C. and stirred at this temperature for one hour. The product isfiltered off and washed twice with 2.4 l of THF each time and twice with3.2 l of water each time. The product is dried at 70° C. under vacuumunder entraining gas.

Yield: 1.501 kg (94% of theory) of an almost colourless powder (veryslight yellow tint).

HPLC method B: RT ca. 6.7 min.

MS (EIpos): m/z=379 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H),3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14(d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 8(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(I) as a solution in acetonitrile/methanol 40:60

Enantiomer Separation on an SMB System

The feed solution is a solution corresponding to a concentrationconsisting of 50 g of racemic4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(XIII), dissolved in 1 liter of a mixture of methanol/acetonitrile60:40.

The solution is chromatographed by means of an SMB system on astationary phase: Chiralpak AS-V, 20 μm. The pressure is 30 bar and amixture of methanol/acetonitrile 60:40 is used as eluent.

9.00 kg of4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(XII) are dissolved in 180 l of a mixture consisting ofmethanol/acetonitrile 60:40 and chromatographed by means of SMB. Afterconcentrating the product-containing fractions, 69.68 liters of a 6.2%solution (corresponding to 4.32 kg of(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(I) is obtained as a solution in acetonitrile/methanol 40:60).

Yield: 4.32 kg (48% of theory), as a colourless fraction dissolved in69.68 liters of acetonitrile/methanol 40:60.

Enantiomeric purity: >98.5% e.e. (HPLC, method D)

A sample is concentrated under vacuum and gives: MS (EIpos): m/z=379[M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H),3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14(d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 9(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthridine-3-carboxamide(I)

Crystallization and Polymorph Adjustment

64.52 liters of a 6.2% solution from Example 8 in a mixture ofacetonitrile/methanol 40:60 (corresponding to 4.00 kg of compound 1)were filtered through a filter cartridge (1.2 um) and subsequentlysufficiently concentrated at 250 mbar such that the solution is stillstirrable. 48 l of ethanol, denatured with toluene, was added anddistilled again at 250 mbar up to the limit of stirrability(redistillation in ethanol). A further 48 l of ethanol, denatured withtoluene, was added and then distilled off at atmospheric pressure downto a total volume of ca. 14 l (jacket temperature 98° C.). The mixturewas cooled via a gradient (4 hours) to 0° C., stirred at 0° C. for 2hours and the product filtered off. The product was washed twice with 4l of cold ethanol each time and then dried at 50° C. under vacuum.

Yield: 3.64 kg (91% of theory) of a colourless crystalline powder.

Enantiomeric purity: >>99% e.e. (HPLC method D); Retention times/RRT:(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-16-naphthyridine-3-carboxamide(1) ca. 11 min. RRT: 1.00;(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(I) ca. 9 min. RRT: 0.82

Purity: >99.8% (HPLC method B), RT: ca. 6.7 min.

Content: 99.9% (relative to external standard)

specific rotation (chloroform, 589 nm, 19.7° C., c=0.38600 g/100 ml):−148.8°.

MS (EIpos): m/z=379 [M+H]⁺

¹H NMR (300 MHz, DMSO-d₆): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H),3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14(d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Melting point: 252° C. (compound of the formula (I) in crystalline formof polymorph I)

Physicochemical Characterization of Compound of the Formula (I) inCrystalline Form of Polymorph I

Compound of the formula (I) in crystalline form of polymorph I melts at252° C., ΔH=95-113 Jg⁻¹ (heating rate 20 Kmin⁻¹, FIG. 1 ).

A depression of the melting point was observed depending on the heatingrate.

The melting point decreases at a lower heating rate (e.g. 2 Kmin⁻¹)since decomposition occurs.

No other phase transitions were observed. A loss of mass of ca. 0.1% wasobserved up to a temperature of 175° C.

Stability and Moisture Absorption

Samples of compound of the formula (I) in crystalline form of polymorphI were stored at 85% and 97% rel. humidity (25° C.). The samples wereevaluated after 12 months by DSC, TGA and XRPD. After 12 months, a masschange of <0.1% is observed in both cases. This means that compound ofthe formula (I) in crystalline form of polymorph I shows no significantabsorption of water under these storage conditions. According to DSC,TGA and XRPD, no difference exists in compound of the formula (I) incrystalline form of polymorph I.

Pharmaceutical formulation of(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamideof the formula (I)

A granular solution of the compound of the formula (I) in crystallineform of polymorph I in micronized form, hypromellose 5 cP and sodiumlauryl sulphate was prepared in purified water.

Microcrystalline cellulose, lactose monohydrate and croscarmellosesodium were mixed (premix) in a container or a fluidized bed granulator.

The premix and the granular solution were granulated in the fluid-bedgranulator.

The lubricant magnesium stearate was added after which the granulate wasdried and sieved. A ready to press mixture was thus prepared.

The ready to press mixture was compressed to give tablets using a rotarytablet press.

A homogeneous coating suspension was prepared from hypromellose, talc,titanium dioxide, yellow iron oxide, red iron oxide and purified water.The coating suspension was sprayed onto the tablets in a suitablecoating device.

Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Composition [mg] [mg][mg] [mg] [mg] [mg] [mg] Compound 1.25 2.50 5.00 7.50 10.00 15.00 20.00of the formula (I) in polymorph I micronized Excipients Microcrystalline73.80 72.50 69.90 67.30 64.70 62.00 59.30 cellulose Croscarmellose 4.504.50 4.50 4.50 4.50 4.50 4.50 sodium Hypromellose 5 cP 4.50 4.50 4.504.50 4.50 4.50 4.50 Lactose monohydrate 45.00 45.00 45.00 45.00 45.0042.50 40.00 Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90 Sodiumlauryl 0.05 0.10 0.20 0.30 0.40 0.60 0.80 sulphate Weight (uncoated130.00 130.00 130.00 130.00 130.00 130.00 130.00 tablet) Film-coatingHypromellose 5 cP 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336Titanium dioxide 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 Talc0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 Yellow iron oxide0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 Red iron oxide 0.00720.0072 0.0072 0.0072 0.0072 0.0072 0.0072 Weight (film- 6.0000 6.00006.0000 6.0000 6.0000 6.0000 6.0000 coating) Weight (coated 136.00 136.00136.00 136.00 136.00 136.00 136.00 tablet)HPLC Conditions/MethodsMethod A

YMC Hydrosphere C18

150*4.6 mm, 3.0 μm

25° C., 1 ml/min, 270 nm, 4 nm

0′: 70% TFA 0.1%*; 30% acetonitrile

17′: 20% TFA 0.1%*; 80% acetonitrile

18′: 70% TFA 0.1%*; 30% acetonitrile

*: TFA in water

Method B

YMC Hydrosphere C18

150*4.6 mm, 3.0 μm

25° C., 1 ml/min., 255 nm, 6 nm

0′: 90% TFA 0.1%; 10% acetonitrile

20′: 10% TFA 0.1%; 90% acetonitrile

18′: 10% TFA 0.1%; 90% acetonitrile

Method C

Nucleodur Gravity C18

150*2 mm, 3.0 μm

35° C.; 0.22 ml/min., 255 nm, 6 nm

Solution A: 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammoniumdihydrogen

phosphate in 1 L of water (ammonium phosphate buffer pH 7.2)

Solution B: acetonitrile

0′: 30% B; 70%/A

15′: 80% B; 20% A

25′: 80% B; 20% A

Method D

Column length: 25 cm

Internal Diameter: 4.6 mm

Packing: Chiralpak IA, 5 μm

Reagents: 1. Acetonitrile HPLC grade

2. Methyl tert-butyl ether (MTBE), p.a.

Test solution The sample is dissolved at a concentration of 1.0 mg/mL

in acetonitrile.

(e.g. ca. 25 mg of sample, weighed exactly, dissolved in acetonitrile to25.0 mL).

Eluent A. acetonitrile

B. Methyl tert-butyl ether (MTBE), p.a.

Flow rate 0.8 ml/min

Column oven temperature 25° C.

Detection measuring wavelength: 255 nm

Band width: 6 nm

Injection volumes 5 μL

Mix composition of eluents A and B in ratio by volume of 90:10

Chromatogram run time 30 min

Retention times/RRT:

(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(1) ca. 11 min. RRT: 1.00

(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(1) ca. 9 min. RRT: 0.82

Lattice Constants of Compound of the Formula (I) in Crystalline Form ofPolymorph I

Polymorph I

Crystal system orthorhombic

Space group P2(1)2(1)2(1)

Molecules per unit

cell 4

Length of axis a [Å] 7.8610(3)

Length of axis b [Å] 11.7797(6)

Length of axis c [Å] 20.1792(8)

α [°] 90

β [°] 90

γ [°] 90

Calculated density at

100 K [g cm-3] 1.345

Measuring Parameters of the X-ray Diffractometry for the Measurement ofCompound of the Formula (I) in Crystalline Form of Polymorph I

Data set name 2429-08a r2 Scan axis 2Theta-Omega Start position [°2Th.]2.0000 End position [°2Th.] 37.9900 Type of divergence screen Fixed Sizeof divergence screen [°] 1.0000 Measurement temperature [° C.] 25 Anodematerial Cu K-Alpha1 [Å] 1.54060 Generator setting 35 mA, 45 kVDiffractometer type Transmission diffractometer Goniometer radius [mm]240.00 Focus-div. screen gap [mm] 91.00 Primary beam monochromator YesSample rotation Yes

Peak maximum [2 Theta] Polymorph I 8.5 11.4 11.9 13.4 14.1 14.8 15.015.4 16.0 17.2 18.5 19.0 19.8 20.5 20.8 22.1 22.7 23.0 23.1 23.6 23.924.6 24.9 25.2 25.6 26.0 26.5 27.1 27.3 28.3 28.5 28.8 29.6 30.1 30.631.5 31.9 32.4 32.9 33.1 33.4 33.7 34.5 34.7 35.0 35.8 36.2 36.5 37.237.4Measuring Conditions for the IR and Raman Spectroscopy for theMeasurement of the Compound of the Formula (I) in Crystalline Form ofPolymorph I:IR:

Instrument Perkin Elmer Spectrum One Number of scans 32 Resolution 4cm⁻¹ Technique Diamond ATR unit Raman: Instrument Bruker Raman RFS 100/SNumber of scans 64 Resolution 2-4 cm⁻¹ Laser Power 350 mW Laserwavelength 1064 nm

Band maximum [cm⁻¹] IR-ATR Raman Polymorph I Polymorph I 3475 3074 34162997 3366 2970 3074 2941 2992 2920 2952 2836 2835 2231 2230 1659 16811641 1658 1623 1606 1601 1572 1577 1485 1487 1464 1443 1454 1383 14311362 1420 1327 1407 1303 1381 1267 1355 1230 1341 1191 1325 1161 13031123 1285 1093 1267 1032 1255 991 1229 883 1222 827 1161 810 1136 7591097 734 1031 708 991 671 976 613 967 528 924 505 909 471 875 442 847346 827 320 810 297 776 186 758 155 746 114 733 723 706 697 670

DESCRIPTION OF THE FIGURES

FIG. 1 : DSC (20 Kmin⁻¹) and TGA of compound of the formula (I) incrystalline form of polymorph I

FIG. 2 : X-ray of a single crystal of polymorph I of(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide(1)

FIG. 3 : X-ray diffractogram of compound of the formula (I) incrystalline form of polymorph I

FIG. 4 : Raman spectrum of compound of the formula (I) in crystallineform of polymorph I

FIG. 5 : FT-Infrared (IR) spectrum (KBr) of compound of the formula (I)in crystalline form of polymorph I

FIG. 6 : FT-Infrared (IR) spectrum (ATR) of compound of the formula (I)in crystalline form of polymorph I

FIG. 7 : FT-Near-infrared (NIR) spectrum of compound of the formula (I)in crystalline form of polymorph I

FIG. 8 : FT-Far-infrared (FIR) spectrum of compound of the formula (I)in crystalline form of polymorph I

FIG. 9 : Solid state ¹³C-NMR spectrum of compound of the formula (I) incrystalline form of polymorph I

FIG. 10 : Stability of compound of the formula (I) in crystalline formof polymorph I in air humidity (x-axis % relative humidity/y-axis weightchange in %

The invention claimed is:
 1. A process for preparing a compound offormula (VI)

comprising reacting a compound of formula (XIV) or formula (XlVa)

with dimethyl sulphate to give a compound of formula (XV) or (XVa)

reducing the non-isolated methyl esters of the formula (XV) or (XVa)with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminiumdihydride) and 1.28 equivalents of N-methylpiperazine to give analdehyde of formula (XVI) or (XVIa)

and reacting the aldehyde of formula (XVI) or (XVIa) without isolationto give the compound of formula (VI)


2. A process for preparing compounds of formulae (Villa+b) (VIIIa+b)

comprising dissolving a compound of formula (VI)

in isopropanol (3-7 fold) 3-7 fold, 5-10 mol % of piperidine and 5-10mol % of glacial acetic acid at 30° C. and reacting the dissolvedcompound of formula (VI) with a compound of formula (VII)

to give the compounds of formulae (VIII a+b)


3. A process for preparing a compound of formula (XI)

comprising stirring a compound of formula (X)

with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide at100 to 120° C. for 1.5 to 3 hours to give the compound of formula (XI)


4. A process for preparing a compound of formula (XII)

comprising saponifying a compound of formula (XI)

in a THF/water mixture (2:1, 9-fold) 2:1, 9-fold, with aqueous sodiumhydroxide solution to give the compound of formula (XII)


5. A process for preparing a compound of formula (XIII)

comprising reacting a compound of formula (XII)

in a one-pot reaction in THF by first admixing with carbodiimidazole andcatalytic amounts of 4-(dimethylamino)pyridine to form an admixture,heating the admixture under reflux together with hexamethyldisilazanefor 16 to 24 hours and then in a third step hydrolysing in water withTHF or water to give the compound of formula (XIII)


6. A process for preparing compounds of formulae (VIII a+b):

comprising preparing the compound of formula (VI)

according to the process of claim 1, dissolving the compound of formula(VI) in isopropanol (3-7 fold), 3-7 fold, 5-10 mol % of piperidine and5-10 mol % of glacial acetic acid at 30° C. and reacting the dissolvedcompound of formula (VI) with a compound of formula (VII)

to give the compounds of formulae (VIII a+b):


7. A process for preparing a compound of formula (XI)

comprising preparing the compounds of formulae (VIII a+b) according toclaim 2, reacting the compounds of formulae (VIII a+b) with a compoundof formula (IX)

to give a compound of formula (X)

stirring the compound of formula (X) with 2.5-5 eq of triethylorthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hoursto give the compound of the formula (XI)


8. A process for preparing a compound of formula (XII)

comprising preparing the compound of formula (XI) according to claim 3,saponifying the compound of formula (XI) in a THF/water mixture (2:1,9-fold) 2:1, 9-fold, with aqueous sodium hydroxide solution to give thecompound of formula (XII)


9. A process for preparing a compound of formula (XIII)

comprising preparing the compound of formula (XII)

according to the process of claim 4, reacting the compound of formula(XII) in a one-pot reaction in THF by first admixing withcarbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine toform an admixture, heating the admixture under reflux together withhexamethyldisilazane for 16 to 24 hours and then in a third stephydrolysing in water with THF or water to give the compound of formula(XIII)


10. A process for preparing a compound of formula (XI)

comprising preparing compounds of formulae (VIII a+b)

according to the process of claim 6 reacting the compounds of formulae(VIII a+b) with a compound of formula (IX)

to give a compound of formula (X)

stirring the compound of formula (X) with 2.5-5 eq of triethylorthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hoursto give a compound of formula (XI)


11. A process for preparing the compound of formula (XII)

comprising preparing the compound of formula (XI) according to claim 7,and saponifying the compound of formula (XI) in a THF/water mixture(2:1, 9-fold) 2:1, 9-fold, with aqueous sodium hydroxide solution togive the compound of formula (XII)


12. A process for preparing a compound of formula (XIII)

comprising preparing the compound of formula (XII)

according to the process of claim 8, reacting the compound of formula(XII) in a one-pot reaction in THF by first admixing withcarbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine toform an admixture, heating the admixture under reflux together withhexamethyldisilazane for 16 to 24 hours and then in a third stephydrolysing in water with THF or water to give the compound of formula(XIII)


13. A process for preparing a compound of formula (XII)

comprising preparing the compound of formula (XI)

according to the process of claim 10, saponifying the compound offormula (XI) in a THF/water mixture (2:1, 9-fold) 2:1, 9-fold, withaqueous sodium hydroxide solution to give a compound of formula (XII)


14. A process for preparing a compound of formula (XIII)

comprising preparing the compound of formula (XII)

according to the process of claim 11, reacting the compound of formula(XII) in a one-pot reaction in THF by first admixing withcarbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine toform an admixture, heating the admixture under reflux together withhexamethyldisilazane for 16 to 24 hours and then in a third stephydrolysing in water with THF or water to give the compound of formula(XIII)


15. A process for preparing a compound of formula (XIII)

comprising preparing the compound of formula (XII)

according to the process of claim 13, reacting the compound of formula(XII) in a one-pot reaction in THF by first admixing withcarbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine toform an admixture, heating the admixture under reflux together withhexamethyldisilazane for 16 to 24 hours and then in a third stephydrolysing in water with THF or water to give the compound of formula(XIII)


16. A process for preparing a compound of formula (I)

comprising preparing the compound of formula (XIII) in a mixture ofenantiomers according to the process of claim 5 and isolating thecompound of formula (I) from the mixture.
 17. A process for preparing acompound of formula (I)

comprising preparing the compound of formula (XIII) in a mixture ofenantiomers according to the process of claim 9 and isolating thecompound of formula (I) from the mixture.
 18. A process for preparing acompound of formula (I)

comprising preparing the compound of formula (XIII) in a mixture ofenantiomers according to the process of claim 12 and isolating thecompound of formula (I) from the mixture.
 19. A process for preparing acompound of formula (I)

comprising preparing the compound of formula (XIII) in a mixture ofenantiomers according to the process of claim 14 and isolating thecompound of formula (I) from the mixture.
 20. A process for preparing acompound of formula (I)

comprising preparing the compound of formula (XIII) in a mixture ofenantiomers according to the process of claim 15 and isolating thecompound of formula (I) from the mixture.
 21. The process of claim 17,wherein the isolated compound of the formula (I) is present in one ormore polymorphs or as a solvate in an inert solvent, further comprisingstirring the inert solvent containing the isolated compound of formula(I) at a temperature of 20° C.-120° C. and isolating the compound of theformula (I) as crystalline polymorph I.
 22. The process of claim 18,wherein the isolated compound of the formula (I) is present in one ormore polymorphs or as a solvate in an inert solvent, further comprisingstirring the inert solvent containing the isolated compound of formula(I) at a temperature of 20° C.-120° C. and isolating the compound of theformula (I) as crystalline polymorph I.
 23. The process of claim 19,wherein the isolated compound of the formula (I) is present in one ormore polymorphs or as a solvate in an inert solvent, further comprisingstirring the inert solvent containing the isolated compound of formula(I) at a temperature of 20° C.-120° C. and isolating the compound of theformula (I) as crystalline polymorph I.
 24. The process of claim 20,wherein the isolated compound of the formula (I) is present in one ormore polymorphs or as a solvate in an inert solvent, further comprisingstirring the inert solvent containing the isolated compound of formula(I) at a temperature of 20° C.-120° C. and isolating the compound of theformula (I) as crystalline polymorph I.